Chikungunya virus (CHIKV) is a reemerging alphavirus that recently spread throughout the world via its mosquito vectors. The virus has high potential to inflict significant morbidity and mortality worldwide, including the U.S., with initial transmissions reported in Florida. Older adults are particularly sensitive to severe CHIKV disease (CHIKVD), which includes fever, rash, joint pain and sometimes involvement of parenchymal organs (liver, brain, kidney). Moreover, CHIKVD tends to persist in many, particularly older, subjects in the form of highly debilitating arthritis/arthralgia for months and years. While we are beginning to understand CHIKV pathogenesis and immunity, we are far from even scratching the surface on the mechanisms of age-related vulnerability to CHIKV. We recently developed a mouse model which recapitulates age-related clinical outcomes observed in CHIKV-infected elderly humans, and used it to begin to elucidate mechanisms underlying the age-related dysfunction of the immune response to CHIKV infection. We found decreased production of CXCL9 and an increase in TGF?, concomitant with qualitative and quantitative impairments in B and T cell responses which failed to clear the virus. We showed that anti-TGF? antibody blockade could prevent the age-related increase in CHIKV disease severity, reduce joint pathology and improve production of neutralizing antibodies. TGF? was also elevated and neutralizing Ab reduced in older humans suffering from CHIKV, making our model potentially directly relevant to older adults. Here, we propose to dissect mechanisms that lead to dysregulated TGF? production and to elucidate how TGF? contributes to increased pathology and decreased CHIKV control. Our central hypothesis is that in old CHIKV-infected mice, increased TGF? and reduced CXCL9 levels interact and/or synergistically dysregulate immunity against CHIKV by acting upon Th1, B and Treg cells. This hypothesis and related questions and sub-hypotheses will be tested in the following Aims: Aim 1. To test whether and how age-related defects in adaptive immunity contribute to immunopathology, poor CHIKV control or both. Aim 2. To elucidate how and why TGF? is dysregulated with aging during CHIKV infection. Aim 3. To define how TGF? impairs adaptive immunity CHIKV and precipitates joint pathology with age. These experiments will provide detailed insights into pathogenesis and immunity against CHIKV in old organisms, paving way for immune interventions against CHIKVD/chronic arthritis in older adults.